AU2014283879B2 - Benzimidazole-2-piperazine heterocyclic compound, pharmaceutical composition thereof, preparation method and use thereof - Google Patents

Benzimidazole-2-piperazine heterocyclic compound, pharmaceutical composition thereof, preparation method and use thereof Download PDF

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AU2014283879B2
AU2014283879B2 AU2014283879A AU2014283879A AU2014283879B2 AU 2014283879 B2 AU2014283879 B2 AU 2014283879B2 AU 2014283879 A AU2014283879 A AU 2014283879A AU 2014283879 A AU2014283879 A AU 2014283879A AU 2014283879 B2 AU2014283879 B2 AU 2014283879B2
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benzimidazole
piperazin
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Xing Fan
Jihong QIN
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Shanghai Huilun Life Science & Technology Co Ltd
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract

Disclosed are a benzimidazole-2-piperazine heterocyclic derivative, preparation method and medical use thereof. Particularly disclosed are a new benzimidazole-2-piperazine heterocyclic derivative as represented by general formula (I), preparation method thereof, pharmaceutical composition comprising the same, and use of the derivative as a therapeutic agent, particularly as a poly (ADP-ribose) polymerase (PARP) inhibitor.

Description

BENZIMIDAZOLE-2-PIPERAZINE HETEROCYCLIC COMPOUND, PHARMACEUTICAL COMPOSITION CONTAINING THE SAME, PREPARATION METHOD AND USE THEREOF
Technical Field
The present invention relates to a benzimi.dazole-2-piperazine heterocyclic compound, a preparation method, a pharmaceutical composition containing the same, and use thereof as a therapeutic agent and a poly(ADP-ribose) polymerase (PARP) inhibitor.
Related Art
Chemotherapeutics and ionizing radiation are two ways commonly used in the treatment of cancers. The two therapies both cause DNA single strand and/or double strand break, and thus exert a cytotoxic effect, resulting in the death of target tumor cells due to chromosome damage. In response to DNA damage, an important consequence is the activation of cell cycle checkpoint signaling for the purpose of protecting the cells against mitosis in case of DNA damage, thereby avoiding cell damage. In most cases, the tumor cells have a high proliferation rate while exhibiting deficiency in cell cycle checkpoint signaling. Therefore, it can be inferred that a specific mechanism of DNA repair exists in the tumor cells, which may rapidly respond to and repair the chromosome damage associated with proliferation regulation, such that the tumor cells survive the cytotoxic effect of some therapeutic agent.
In clinical use, the concentration of the chemotherapeutic agent or the intensity of the radiation is effective for counteracting the mechanism of DNA repair, to ensure the killing effect on target tumor cells. However, resistance to treatment may be developed in the tumor cells through a strengthened mechanism of DNA damage repair, such that the tumor cells survive the fatal DNA damage. To overcome the resistance development, the dose of the therapeutic agent or the intensity of the radiation is generally required to be enhanced. This has a detrimental effect on normal tissues around the lesion, whereby serious adverse effects are implicated during treatment, and the treatment risk is increased. Meanwhile, the therapeutic effect is decreased with increasing resistance. Therefore, it can be inferred that the cytotoxic effect of a DNA damaging agent may be improved in a tumor cell-specific manner by regulating the DNA damage signaling and repair mechanism.
Poly(ADP-ribose)polymerases (PARPs) characterized by poly(ADP~ribosyi)ation activity constitute a super family of 18 intranuclear and cytoplasmic enzymes. Through this poly(ADP-ribosy!)ation, the catalytic activity of target proteins and the protein-protein interactions may be modulated, and some fundamental biological processes are regulated, including DNA repair, and cell death. Moreover, the genomic stability also correlates with the poly( ADP-ribosyl)ation. PARP-1 activity accounts for about 80% of the total PA.RP activity in the cells. PARP-1 and PARP-2 closest thereto are members in the PARP family that have an ability to repair the DNA damage. As a sensor and signaling protein of DNA damage, PARP-1 can quickly detect and directly bind to the site of DNA damage, followed by inducing the aggregation of numerous proteins required for DNA repair, such that the DNA damage is repaired. When PARP-1 is deficient in the cells, PARP-2 is able to repair the DNA damage in place of PARP-1. Studies show that compared with normal cells, PARPs are expressed at a generally increased level in solid tumors. Furthermore, cancers (e.g. breast and ovary cancer) which are deficient in DNA repair-related genes (e.g. BRCA-1 or BRCA-2) are extremely sensitive to the PARP-1 inhibitor, indicating that the PARP inhibitor, as a single therapeutic agent, is potentially useful in the treatment of triple negative breast cancer. Moreover, since the mechanism of DNA damage repair is a principal mechanism through which resistance is developed in the tumor cells counteracting the chemotherapeutic agent and ionizing radiation. Accordingly, PARP-1 is considered to be a target of interest in seeking a new method for treating cancers.
The PARP inhibitors that are developed and designed previously are analogues developed with nicotinamide of NAD that is a substrate for PARP as a template. These inhibitors are competitive inhibitors of NAD, which compete with NAD for the catalytic sites of PARP, thereby hindering the synthesis of poly(ADP-ribose) chain. Without the modification with poly(ADP-ribosyl)ation, PARP cannot be cleaved from the site of DNA damage, such that other proteins involved in repair cannot access the site of damage and thus the repair process cannot be performed. Therefore, under attack of cytotoxic agents or radiation, the presence of the PARP inhibitor ultimately leads to the death of tumor cells with impaired DNA.
In addition, NAD, consumed as a substrate for PARP, is essential to the synthesis of ATP in cells. At a high level of PARP activity, the intracellular NAD level decreases dramatically, thus affecting the ATP level in cells. Due to the inadequate content of ATP in the cells, the cells are failed in ATP-dependent programmed cell death, and have to turn to necrosis, a special apoptosis process. During necrosis, a large amount of inflammatory factors are released, causing a toxic effect to other organs and tissues. Therefore, the PARP inhibitor may find use in the treatment of many diseases associated with such a mechanism, including neurodegenerative diseases (for example, senile dementia, Huntington's disease, and Parkinson's disease), diabetes, ischemia or complications during ischemic reperfusion, for example, myocardial infarction and acute renal failure, diseases of circulatory system, for example, septic shock, and inflammatory diseases such as chronic rheumatism.
In this specification, references to prior art are not intended to acknowledge or suggest that such prior art is widely known or forms part of the common general knowledge in the field either in Australia or elsewhere.
SUMMARY
In one aspect there is provided A benzimidazole-2-piperazine heterocyclic compound of general Formula (I) or a pharmaceutically acceptable salt thereof:
(I) wherein in general Formula (I): R is fluoro; one of X, Y, and Z is nitrogen, and the others are CH; or X, Y, and Z are all CH;
Ri is hydrogen, Ci-Cg alkyl, methoxy, trifluoromethyl, halo, nitro, cyano, CONR2R3, and NR2R3; R2 is hydrogen, or C1-C6 alkyl; and R3 is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, or NR2R3 are cyclized to form morpholinyl, tetrahydropyrrolyl, and piperidinyl.
Disclosed herein is a new benzimidazole-2-piperazine heterocyclic compound and a derivative thereof, as well as their tautomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, metabolites and metabolic precursors or prodrugs.
Also disclosed herein is a pharmaceutical composition comprising the benzimidazole-2-piperazine heterocyclic compound as an active ingredient.
Also disclosed herein is a method for preparing the benzimidazole-2-piperazine heterocyclic compound.
Also disclosed herein is use of the benzimidazole-2-piperazine heterocyclic compound in the preparation of drugs.
In a first aspect of the present invention, a benzimidazoie-2-piperazine heterocyclic compound of general Formula (I) is provided :
(I) where in general Formula (i), R is hydrogen or halo, one of X, Y, and Z is nitrogen, and the others are CH or X, Y, and Z are all CH;
Rt is hydrogen, Ci-Ce alkyl, methoxy, trifluoromethyl, halo, nitro, cyano, CQNR2R3, and NR2R3; R2 is hydrogen, or Ci-G, alkyl; and R.3 is hydrogen, C1-C6 alkyl, or Cs-Ce cycloalkyl, or NR2R3 are cyelized to form morpholinyl, tetrahydropyrrolyl, and piperidinyl.
Further preferably, in the compound of general Formula (I) provided in the present invention, R is hydrogen or fluoro; one of X, Y, and Z is nitrogen, and the others are CH, or X, Y, and Z are all CH;
Ri is hydrogen, C1-C4 alkyl, methoxy, trifluoromethyl, fluoro, nitro, cyano, CONR.2R3, and NR2R3; R2 is hydrogen, or C1-C4 alkyl; and R3 is hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl, or NR.2R3 are cyelized to form morpholinyl, and tetrahydropyrrolyl.
Most preferably, the compound of general Formula (I) according to the present invention is Compounds (1)-(37) below:
The compound of general Formula (I) is any one of an enantiomer, a diastereoisomer, and a conformer, or a mixture of two or more thereof.
The compound of general Formula (I) is a pharmaceutically acceptable derivative.
The compound of general Formula (I) according to the present invention may exist as a pharmaceutically acceptable salt.
The pharmaceutically acceptable salt according to the present invention is a hydrochloride, a sulfate, a phosphate, an acetate, a trifluoroacetate, a methanesulfonate, a trifluoromethanesulfonate, a p-toluenesulfonate, a tartrate, a maieate, a fumarate, a succinate or a malate of the compound of general Formula (I).
In a preferred embodiment of the present invention, the benzimidazole-2-piperazme heterocyclic compound of general Formula (I) is a 2-(piperazm-l-yl)-IH-benzimidazo3e-4-carboxamide compound and a pharmaceutically acceptable salt thereof.
In a second aspect of the present invention, a method for preparing the compound of general Formula (I) is provided. The reaction scheme is as follows:
where R and Ri are as defined above. The method comprises specifically:
Step 1): cyclizing substituted methyl 2, 3-diaminobenzoate with earbonyldiimidazole, to obtain substituted methyl 2-oxo-2,3-dihydro-lH-benzimidazole-4-carboxylate (II);
Step 2): chlorinating the substituted methyl 2-oxo-2,3-dihydro-lH-benzimidazole-4-carboxylate (II) obtained in Step 1) through reaction with phosphorus oxychloride, to obtain substituted methyl 2-chloro-1 H-benzimidazole-4-carboxyiate (HE);
Step 3): subjecting the substituted methyl 2-chloro-lH-benzimidazole-4-carboxylate (III) obtained in Step 2) to nucleophilic substitution with piperazine in the presence of a base, to obtain substituted methyl 2-(piperazin-l-yi)-lH-benzimidazole-4-carboxylate (IV);
Step 4): amino lyzing the ester group of the substituted methyl 2-(piperazin-1 -yl)-1 H-benzimidazole-4-carboxylate (IV) obtained in Step 3) in a methanolic ammonia solution, to obtain substituted 2-(piperazin-l-yl)-lH-benzimidazole-4-carboxamide (V); and
Step 5): coupling the substituted 2-(piperazin-1 -yl)- lH-benzimidazole-4-carboxamide (V) obtained in Step 4) with an acid, or reductively aminating the substituted 2-(piperazin-l-yl)-lH-benzimidazole-4-carboxamide (V) obtained in Step 4) with an aldehyde, to generate the compound of general Formula (I).
In a third aspect, a pharmaceutical composition is provided, which comprises a therapeutically effective amount of the compound of general Formula (I) as the active ingredient and one or more pharmaceutically acceptable carriers and/or diluents, or comprises a therapeutically effective amount of the compound of general Formula (I) as the active ingredient and a pharmaceutically acceptable carrier, excipient, or diluent.
In the third aspect, a pharmaceutical composition is provided, which comprises a therapeutically effective amount of a pharmaceutically acceptable derivative of the compound of general Formula (I) or a pharmaceutically acceptable salt thereof as the active ingredient and one or more pharmaceutically acceptable carriers and/or diluents, or comprises a therapeutically effective amount of a pharmaceutically acceptable derivative of the compound of general Formula (I) as the active ingredient and a pharmaceutically acceptable carrier, excipient, or diluent.
In the third aspect, a pharmaceutical composition is provided, which comprises a therapeutically effective amount of a pharmaceutically acceptable salt of the compound of general Formula (I) as the active ingredient and one or more pharmaceutically acceptable carriers and/or diluents, or comprises a therapeutically effective amount of a pharmaceutically acceptable salt of the compound of general Formula (I) as the active ingredient and a pharmaceutically acceptable carrier, excipient or diluent.
The pharmaceutical composition may be prepared into tablets, capsules, an aqueous suspension, an oily suspension, a dispersible powder, granules, lozenges, an emulsion, a syrup, a cream, an ointment, a suppository or an injection.
In the pharmaceutical composition, the compound of general Formula (I) may exist in free form.
In a fourth aspect of the present invention, use of the compound of general Formula (I) in the preparation of drugs for treating diseases that are ameliorated through inhibition of the PARP activity is provided.
In the fourth aspect of the present invention, use of a pharmaceutically acceptable derivative of the compound of general Formula (I) in the preparation of drugs for treating diseases that are ameliorated through inhibition of the P ARP activity is provided.
In the fourth aspect of the present invention, use of a pharmaceutically acceptable salt of the compound of general Formula (I) in the preparation of drugs for treating diseases that are ameliorated through inhibition of the PARP activity is provided.
In the fourth aspect of the present invention, use of the pharmaceutical composition in the preparation of drugs for treating diseases that are ameliorated through inhibition of the PARP activity is provided.
The diseases that are ameliorated through inhibition of the PARI51 activity include vascular diseases, septic shock, ischemic damage, neurotoxic symptoms, hemorrhagic shock, inflammatory disease or multiple sclerosis.
In the fourth aspect of the present invention, use of the compound of general Formula (I) in the preparation of adju vant drugs for treating tumors is provided.
In the fourth aspect of the present invention, use of a pharmaceutically acceptable derivative of the compound of general Formula (I) in the preparation of adjuvant drugs for treating tumors is provided.
In the fourth aspect of the present invention, use of a pharmaceutically acceptable salt of the compound of general Formula (I) in the preparation of adjuvant drugs for treating tumors is provided.
In the fourth aspect of the present invention, use of the pharmaceutical composition in the preparation of adjuvant drugs for treating tumors is provided.
In the fourth aspect of the present invention, use of the compound of general Formula (I) in the preparation of drugs for boosting tumor radiotherapy is provided.
In the fourth aspect of the present invention, use of a pharmaceutically acceptable derivative of the compound of general Formula (I) in the preparation of drugs for boosting tumor radiotherapy is provided.
In the fourth aspect of the present invention, use of a pharmaceutically acceptable salt of the compound of general Formula (I) in the preparation of drugs for boosting tumor radiotherapy is provided.
In the fourth aspect of the present invention, use of the pharmaceutical composition in the preparation of drugs for boosting tumor radiotherapy is provided.
In the fourth aspect of the present invention, use of the compound of general Formula (I) in the preparation of chemotherapeutic agents for tumors is provided.
In the fourth aspect of the present invention, use of a pharmaceutically acceptable derivative of the compound of general Formula (I) in the preparation of chemotherapeutic agents for tumors is provided.
In the fourth aspect of the present invention, use of a pharmaceutically acceptable salt of the compound of general Formula (I) in the preparation of chemotherapeutic agents for tumors is provided.
In the fourth aspect of the present invention, use of the pharmaceutical composition in the preparation of chemotherapeutic agents for tumors is provided.
In the fourth aspect of the present invention, use of the compound of general Formula (I) in the preparation of drugs for treating an individual with a cancer which is deficient in Homologous Recombination (HR) dependent DNA double strand break (DSB) repair is provided.
In the fourth aspect of the present invention, use of a pharmaceutically acceptable derivative of the compound of general Formula (I) in the preparation of drugs for treating an individual with a cancer which is deficient in Homologous Recombination (HR) dependent DNA double strand break (DSB) repair is provided.
In the fourth aspect of the present invention, use of a pharmaceutically acceptable salt of the compound of general Formula (I) in the preparation of drugs for treating an individual with a cancer which is deficient in Homologous Recombination (HR) dependent DNA double strand break (DSB) repair is provided.
In the fourth aspect of the present invention, use of the pharmaceutical composition in the preparation of drugs for treating an individual with a cancer which is deficient in Homologous Recombination (HR) dependent DNA double strand break (DSB) repair is provided.
Preferably, the cancer comprises one or more cancer cells having a reduced or abrogated ability to repair DNA DSB by HR relative to normal cells.
Preferably, the cancer has a BRCA-1 or BRCA-2 deficient mutant phenotype.
Preferably, the cancer is breast, ovary, pancreas or prostate cancer.
To examine the degree of inhibition of the compounds provided in the present invention on the PARP enzyme, the activity of the compounds of the present invention for PARP enzyme are determined through biological enzyme activity assay. PARP is an enzyme responsible for post-translational modification, which may be activated by means of DNA damage. The process catalyzed by PARP in vivo is mainly NAD-dependent poly(ADP-ribosyl)ation, in which the substrates are mainly some nuclear proteins including PARP, one example of which is histone. In the present invention, the PARP activity is assayed by determining the poly(ADP-ribosyl)ation degree of histone coated in a 96-well plate in the presence of NAD, and the P ARP activity under the action of a PARP inhibitor is correspondingly assayed, thereby evaluating the degree of inhibition of the compounds on PARP activity.
DETAILED DESCRIPTION
The terms used in the description and claims have the following meanings, unless stated otherwise.
In the present invention, the term “Ci-Co alkyl” refers to a saturated linear or branched monovalent hydrocarby! group having 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, and t-butyl.
The term “halogen” and “halo” refer to F, CL Br, and I. “Pharmaceutically acceptable salt” refers to a salt that retains the biological effectiveness and properties of the parent compound. The salt includes: (I) acid addition salts, obtainable through reaction of the parent compound as a free base with an inorganic acid including hydrochloric, hydrobromic, nitric, phosphoric, metaphosphoric, sulfuric, sulfurous, perchloric acid and the like; or an organic acid including acetic, propionic, acrylic, oxalic, (d) or (L)-malic, fumaric, maleic, hydroxy benzoic, γ-hydroxybutyric, methoxy benzo ic, phthalic, methanesulfonic, ethanesulfonic, naphthalene-1-sulfonic, naphthalene-2-sulfonic, p-toluenesulfonic, salicylic, tartaric, citric, lactic, mandelic, succinic or malonic acid ; or (2) salts formed by replacing the acidic proton present in the parent compound with a metal ion, for example, alkali metal ion, alkaline earth metal ion or aluminum ion; or through coordination with an organic base, for example, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methyl glucosamine, and the like. “Pharmaceutical composition” refers to a mixture of one or more of the compound according to the present invention or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof with other chemical ingredients, for example, a pharmaceutically acceptable carrier. The pharmaceutical composition is provided for the purpose of promoting the administration of the drug to an animal. “Pharmaceutically acceptable carrier” refers to an inactive ingredient in the pharmaceutical composition that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, for example, but not limited to: calcium carbonate, calcium phosphate, various carbohydrates (e.g. lactose, and mannitol), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic polymers or methacryhc polymers, gel, water, polyethylene glycol, propylene glycol, ethylene glycol, castor oil, hydrogenated castor oil or polyethoxyhydrogenated castor oil, sesame oil, corn oil, and peanut oil.
In addition to the pharmaceutically acceptable carrier, the pharmaceutical composition may further comprises pharmaceutically acceptable adjuvants, for example antibacterial agents, antifungal agents, antimicrobial agents, preservatives, colorants, solubilizers, thickeners, surfactants, chelating agents, proteins, amino acids, lipids, carbohydrates, vitamins, minerals, trace elements, sweeteners, pigments, fragrances or a combination thereof.
In the present invention, a compound and use of the compound as a poly(ADP-ribose) polymerase inhibitor are provided. The process parameters may be appropriately adapted by those skilled in the art based on the disclosures herein. It should be particularly noted that all equivalent replacements and modifications are apparent to those skilled in the art, and contemplated by the present invention. The method and use of the present invention have been described with reference to preferred examples, and it is apparent that the invention may be implemented and applied by persons of skill in the art through modification, or appropriate alternation and combination made to the method and use of the present invention without departing from the disclosures, spirits and scope of the present invention.
Hereinafter, the present invention is further described with reference to examples.
Preparation Examples
Example 1
Preparation of Compound (1): 2~(4-(pyrimidin-2~yl)piperazin-l-yl) -1 H-benzimidazole-4-carboxamide. The reaction scheme was specifically as follows.
Step 1: Preparation of methyl 2-oxo-2,3-dihydro-1 H-benzimidazole-4-carboxylate
To a solution of methyl 2,3-diaminobenzoate (0.8 g, 4.8 mmol) dissolved in anhydrous tetrahydrofuran (20 mL), carbonyldiimidazole (1.56 g, 9.6 mmol) was added, warmed to reflux, and reacted for 8 hrs. After cooling, the solvent was removed under reduced pressure, and the residue was separated by flash column chromatography (petroleum ether: ethyl acetate=5: 1) to obtain Compound a: methyl 2-oxo-2,3~dihydro~lH-benzirnidazole-4-carboxylate as a light solid (0.3 g, yield 33%). MS (ESI) m/z: [M+H]+=193.
Step 2: Preparation of methyl 2-chloro-lH-benzimidazole-4-carboxylate
Compound a: methyl 2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (1.1 g, 5.7 mmol) was added to phosphorus oxychloride (8 ml.), warmed to reflux, and reacted for 8 hrs. After cooling, the solvent was removed under reduced pressure, and the residue was separated by flash column chromatography (petroleum ether: ethyl acetate=5: 1) to obtain Compound b: methyl 2-chloro- lH-benzimidazole-4-carboxylate as a white solid (1.5 g, yield 100%), MS (ESI) m/z: [M+Hf=2ii.
Step 3: Preparation of methyl 2-(piperazin-l-yl)-lH-benzimidazole-4-carboxylate
To Compound b: methyl 2-ehloro-lH-benzimidazole-4-carboxylate (59 mg, 0.28 mmol) dissolved in dimethylformamide (5mL), piperazine (110 mg, 1.12 mmol) was added, warmed to 100°C, and reacted for 8 hrs. After cooling, the solvent was removed under reduced pressure, and the residue was separated by flash column chromatography (dichloromethane: methanol=10: 1) to obtain Compound c: methyl 2-(piperazin-l-y])-lH-benzimidazole-4-carboxyiate as a white solid (100 mg, yield 100%). MS (ESI) m/z: [MfH]+=261.
Step 4: Preparation of 2~(piperazin-l-yl)-lH-benzimidazole-4-earboxamide
To a solution of Compound c. methyl 2-(piperazm-i -yl)-1 H-benzimidazole-4-carboxylate (100 mg, 0.28 mmol) dissolved in tetrahydrofuran (5mL), aqueous ammonia (5mL) was added, warmed to 70°C, sealed, and reacted for 8 hrs. After cooling, the solvent was removed under reduced pressure, and the residue was separated by flash column chromatography (dichloromethane: methanol=10: 1) to obtain Compound d: 2-(piperazin-I-yl)-lH-benzimidazole-4-carboxamide as a white solid (20 mg, yield 28%). MS (ESI) m/z: [M+H]+=246.
Step 5: Preparation of 2-(4-(pyrimidin~2-y!)piperazm-l-yl) -1 H-benzimidazo le-4-carboxam ide
To Compound d: 2-(piperazin-I-yl)-lH-benzimidazole-4-carboxamide (74 mg, 0.3 mmol) dissolved in dimethylformamide (5mL), 2-chloropyrimidine (34 mg, 0.3 mmol) and triethylamine (30 mg, 0.3 mmol) were added, warmed to 100°C, and reacted for 8 hrs. After cooling, the solvent was removed under reduced pressure, and the residue was separated by flash column chromatography (dichloromethane: methanol=i 0: 1) to obtain Compound (1): 2-(4-{pyrimidin-2-yl)piperazin-1 -yl)- lH-benzimidazoie-4-earboxamide (32mg, yield 33%). LC-MS (ESI): m/z 324 (M+i)+. !H NMR (300MHz, DMSO-J6): δ 12.10 (br, 1H), 9.16 (br, 1H), 8.44-8.38 (m, 2H), 7.62-7.54 (m, 2H), 7.36-7.32 (m, IH), 7.01-6.95 (m, 1H), 6.70-6.63 (m, 1H), 3.89 (br, 4H), 3.67 (br, 4H).
Example 2
Preparation of Compound (2): 2-(4-(5-fluoropyrimidin-2-yl)piperazin-l-yl)-lH-benzimidazoie-4-carboxamide
(2)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound d: 2-(piperaziii-l-yl)-lH-benzimidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 2-chloro-5-fluoropynmidme, to obtain Compound (2): 2-(4-(5-fluoropyrimidin-2-yl)piperazin-1 -y 1)-1 H-benzimidazole-4-carboxamide (30 mg, yield 72%). LC-MS (ESI): m/z 342 (M+l)+. NMR (300MHz, DMSO-J6): δ 11.92 (br, 1H), 9.13 (br, 1H), 8.50 (s, 2H), 7.60 (d, 1H, J=7.8Hz), 7.52 (br, 1H), 7.32 (d, 1H, J=7.8Hz), 6.98 (t, 1H, J=7.8Hz), 3.87-3.83 (m, 4H), 3.67-3.64 (m, 4H).
Example 3
Preparation of Compound (3): 2-(4-(5-ethylaminopyrimidin-2-yl)piperazin-1 -yl) -1 H-benzimidazo le-4-carboxamide
(3)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound d: 2-(piperazin-l-yl)-lH-benzimidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 2-chloro-5-ethylaminopyrimidine, to obtain Compound (3): 2-(4-(5-ethylaminopyrimidin-2-yl)piperazin-1 -yl) -1 H-benzimidazole-4-carboxamide (23 mg, yield 42%). LC-MS (ESI); m/z 367 (MM )7 !H NMR (300MHz, DMSGM6): δ 9.08 (br, 1H), 7.92 (s, 2H), 7.78-7.72 (m, 2H), 7.66-7.60 (m, 2H), 7.22-7.16 (m, 1H), 4.71-4.67 (m, 211), 4.19-4.15 (m, 2H), 3.73-3.70 (m, 4H), 2.65-2.60 (m, 2H), 1.37 (t, 3H, 1=4.5Hz).
Example 4
Preparation of Compound (4): 2-(4-(5-acetamidopyrimidin-2-yl)piperazin-l-yl) -1 H-benzimidazo !e-4-carboxamide
(4)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound d: 2-(piperazin-l-yl)-lH-benzimidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 2-chloro-5-acetamidopyrimidine, to obtain Compound (4): 2-(4-(5-acetamidopyrimidin.-2-yl)piperazin-l -yl) -1 H-benzimidazole-4-carboxamide (12 mg, yield 22%). LC-MS (ESI): m/z 381 (M+l)+. 4-1 NMR (300MHz, DMSOM6): δ 11.85 (br, 1H), 9.89 (br, 111). 9.14 (s, IH), 8.54 (s, 2H), 7.60 (d, IH, J::::7.5Hz), 7,51 (br, !H), 7.31 (d, 1H, J=7.5Hz), 6.98 (t, IH, J-7.5Hz), 3.84-3.65 (m, 8H), 2.00 (s, 3H).
Example 5
Preparation of Compound (5): 2-(4-(5-methox3?pyrirnidin-2-yl)piperazin-l-yl) -lH-benzimidazole-4-carboxamide
(5)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound d: 2-(piperazin-1 -yl)- lH-benzimidazole-4-carboxarmde was subjected to aromatic nucleophilic substitution with 2-chloro-5-methoxypyrimidine, to obtain Compound (5): 2-(4-(5-methoxypynmidm-2'yl)piperazin-1 -yl) -1 H-benzimidazole-4-carboxamide (17 mg, yield 41%). LC-MS (ESI): m/z 354 (M+l)+. ’H NMR (300MHz, DMSO-r/6): δ 11.86 (br, 1H), 9.15 (br, 1H), 8.25 (s, 2H), 7.60 (d, 1H, J=7.5Hz), 7.51 (br, 1H), 7.31 (d, 1H, J=7.5Hz), 6.98 (t, 1H, J=7.5Hz), 3.77 (br, 7H), 3.64 (br, 4H).
Example 6
Preparation of Compound (6): 2-(4-(5-ammopyrimidim2-y3)piperazin-l-yl) -1 H-benzimidazo le-4-carboxamide
(6)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound d: 2-(piperazin-j~yl)-lH-benzimidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 2-chloro-5-aminopynmidine, to obtain Compound (6): 2-(4-(5-aminopyrinudin-2-yl)piperazm-l-yl)-lH-benzimidazole-4-carboxamide (190 mg, yield 83%). LC-MS (ESI): m/z 339 (M+l)+. *H NMR. (300MHz, DMSO-iid): δ 9.12 (br, 1H), 7.60-7.25 (m, 7H), 7.00-6.95 (m, 1H), 3.67 (br, 8H).
Example 7
Preparation of Compound (7): 2-(4-(pyrimidin-4-yl)piperazin-l-yl) -1 H-benzimidazo le-4-carboxamide
(7)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound d: 2-(4-(pyrimidin-4-yl)piperazin-l-yl) -lH-benzimidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 4-chloropyrirnidme, to obtain Compound (7): 2-(4-(pynmidm-4-y3)piperazin-l-yi) -lH-benzinudazole-4-carboxamide (25 mg, yield 65%). LC-MS (ESI): m/z 324 (M+l)+. *H NMR (300MHz, DMSCM6): δ 11.85 (br, 1H), 9.09 (br, 1H), 8.53 (s, 1H), 8.22 (d, 1H, J=8.1Hz), 7,60 (d, 1H, J=7.5Hz), 7.50 (br, 1H), 7.33 (d, 1H, J=7.5Hz), 6.99 (t, 1H, J=7.5Hz), 6.91 (d, 1H, J=8.1Hz), 3.80-3.79 (m, 4H), 3.68-3.66 (m, 4H).
Example 8
Preparation of Compound (8): 2-(4-(3-ethylaminopyridin-2-yl)piperazin-l-yl) -1 H-benzimidazo le-4-earboxamide
(8)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound d: 2-(4-(pyrimidin~4-yl)piperazin-l-yl) -1 H-benzimidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 2-chloro-3-ethylaminopyridine, to obtain Compound (8): 2-(4-(3-ethylaminopyridin-2-yl)piperazin-l-y3) -1 H-benzimidazole-4-carboxamide (13 mg, yield 36%). LC-MS (ESI): m/z 366 (M+l)+. 1H NMR (300MHz, DMSG-iM): δ 12.02 (br, 1H), 9.18 (br, 1H), 7.62-7.50 (m, 4H), 7.34-7.31 (m, 1H), 7.00-6.89 (m, 3H), 3.77-3.74 (m, 4H), 3.14-3.10 (m, 4H), 2.00-1.93 (m, 2H), 0.85-0.80 (m, 3H).
Example 9
Preparation of Compound (9): 2-(4-(4-trifluoromethylpyrimidin-2-yl)piperazin-1 -yl) -1 H-benzimidazo le-4-carboxamide
(9)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound d: 2-(4-(pyrimidin-4-yl)piperazin-l-yl) -lH-benzimidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 2-chloro-4-trifluoromethylpyrimidine, to obtain Compound (9): 2-(4-(4-trifluoromethylpyrimidin-2-yl)piperazin-l-yl) -1 H-benzimidazole-4-carboxamide (36 mg, yield 55%). LC-MS (ESI): m/z 392 (M +1)7 *H NMR (300MHz, DMSO-i/6): δ 11.87 (br, 1H), 9.13 (br, 1H), 8.72 (d, 1H, J=4.SHz), 7.61 (d, 1H, J=7.8Hz), 7.53 (br, 1H), 7.33 (d, 1H, J=7.8Hz), 7.07 (d, 1H, J=4.8Hz), 6.99 (t, 1H, J=7.8Hz), 3.94 (br, 4H), 3.69 (br, 4H).
Example 10
Preparation of Compound (10): 2-(4-(6-trifluoromethylpynmidin-4-yl)piperazin-l-yl) -1 H-benzimidazo le-4-carboxamide
(10)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1,
Compound d: 2-{4-(pyrimidin-4-y])piperazin~l-yj) -lH-benzimidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 6-chloro-4-trifluoromethylpynmidine, to obtain Compound (10): 2-{4-(6-trifluGromethylpyrimidin-4-yl)piperazin-l-yl) ~lH-benzimidazole-4-earboxamide (40 mg, yield 61%). LC-MS (ESI): m/z 392 (M+l)\ 1H NMR (300MHz, DMSO-J6): 6 11.88 (br, 1H), 9.12 (br, 1H), 8.66 (s, 1H), 7.61 (d, 1H, J=7.5Hz), 7.53 (br, 1H), 7.35 (s, 1H), 7.33 (d, 1H, J=7.5Hz), 6.99 (t, 1H, J=7,5Hz), 3.92 (br, 4H), 3.69 (br, 4H).
Example 11
Preparation of Compound (11): 2-(4-(5-methylcarbamoylpyridin-2-yl)piperazin-l-y!) ~ 1 H-benzimidazo le-4-earboxamide
(11)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound d: 2-(4-(pyrimidin-4-yl)piperazin-l-yl) -1 H-benzinndazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 6-chloro-3 -methylcarbamoylpyridine, to obtain Compound (11): 2-(4-( 5-methylcarbamoylpyndin-2-yl)piperazin-l-yl) -1 H-benzimidazole-4-carboxamide (15 mg, yield 24%). LC-MS (ESI): m/z 380 (M+l)\ !11 NMR (300MHz, DMSO-J6): δ 11.86 (br, 1H), 9.14 (br, 1H), 8.6 (s, 1H), 8.24 (br, 1H), 7.96 (d, 1H, J=9.6Hz), 7.61 (d, 1H, J=7.8Hz), 7.52 (br, 1H), 7.32 (d, 1H, J=7.8Hz), 7.01-6.92 (m, 2H), 3.77 (br, 4H), 3.67 (br, 4H), 2.74 (d, 3H, d 4.21 Iz).
Example 12
Preparation of Compound (12): 2-(4-(5“Carbamoylpyndin“2“yl)piperazin-!-yl) -1 H-benzimidazo le-4-carboxamide
(12)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound d: 2-(4-(pyrimidm-4-yl)piperazin~l~yl) -lH-benzimidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 6-chloro-3-earbamoylpyridine, to obtain Compound (12): 2-(4-(5-carbaffioylpyndin-2-yl)piperazin-1 -yl) -lH-benzirmdazole-4-carboxamide (25 mg, yield 41%). LC-MS (ESI): m/z 366 (M-Kl)\ 3H NMR (300MHz, DMSO-t/6): 6 11.86 (br, IH), 9.14 (br, IH), 8.64 (s, 1H), 7.99 (d, IH, J=7.8Hz), 7.79 (br, IH), 7.60 (d, IH, J=9.0Hz), 7.51 (br, IH), 7,32 (d, IH, J=7.8Hz), 7.17 (br, IH), 7.01-6.91 (m, 2H), 3.78 (br, 4H), 3.67 (br, 4H).
Example 13
Preparation of Compound (13): 2~(4-(2-trifluoromethy!pyridin~4~yl)piperazin-l-y!) -1 H-benzimidazo le-4-carboxamide
(13)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound d: 2-(4-(pyrimidin-4-yl)piperazin-l-yl) -lH-benzimidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 4-chloro-2-trifluoromethylpyridine, to obtain Compound (13): 2-(4-(2-trifluoromethylpyridin-4-yl)piperazin-1 -yl) -1 H-benzimidazole-4-carboxamide (7 mg, yield 13%). LC-MS (ESI): m/z 391 (M+l)+. ]H NMR (300MHz, DMSO-dS)\ δ 11.88 (br, IH), 9.13 (br, IH), 8.34-8.29 (m, IH), 7.63-7.60 (m, IH), 7.53 (br, IH), 7.35-7.30 (m, 2H), 7.12-7.09 (m, IH), 7.03-6.97 (m, IH), 3.70-3.64 (m, 8H).
Example 14
Preparation of Compound (14): 2-(4-(5-cyanopynmidin-2-yl)piperazin-l-yl) -1 H-benzimidazole-4-carboxamide
(14)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound d: 2-(4-(pyrimidin-4-yl)piperazin-l-yl) -lH-benzimidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 2-chloro-5-cyanopyrimidine, to obtain Compound (14): 2-(4-(5-cyanopyrimidin-2-y !)piperazin-1 -yl) -1 H-benzimidazole-4-carboxamide (40 mg, yield 71%). LC-MS (ESI): m/z 349 (M+l)+ ]H NMR (300MHz, DMSO-Jd}: δ 11.88 (br, 1H), 9.09 (br, 1H), 8.80 (s, 2H), 7.60 (d, 1H, J=7.2Hz), 7.53 (br, 1H), 7.33 (d, 1H, J=7.2Hz), 6.99 (t, 1H, J=7.2Hz), 4.01 (br, 4H), 3.69 (br, 4H).
Example 15
Preparation of Compound (15): 2-(4-(5-dimethylcarbamoylpyridin-2-yl)piperazin-l-yl) -1 H-benzimidazo le-4-carboxamide
(15)
Analogous to the process in Step 5 m Preparation of Compound (1) in Example 1, Compound d: 2-(4-(pyrimidin-4-yl)piperazin-l-yl) -lH-benzimidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 0~ch{oro-3-dimethylearbamoylpyridine, to obtain Compound (15): 2-(4-(5-dimethyicarbamoylpyridin-2-yi)piperazin-l-yl) -lH-benzimidazole-4-carboxamide (35 mg, yield 44%). LC-MS (ESI): m/z 394 (M+l)+. *H NMR (300MHz, DMSO-t/6): 6 12.11 (br, IH), 9.19 (br, 1H), 8.24 (s, 1H), 7.66-7.59 (m, 2Π), 7.53 (br, ϊΗ), 7.34-7.31 (m, 1Η), 7.00-6.91 (m, 2H), 3.73-3.70 (m, 8Π), 2.96 (s, 6H).
Example 16
Preparation of Compound (16): 6-fluoro-2-(4-(pyrimidin-4-yl)piperazin-l-yl)-lH-benzimidazoie-4-carboxamide. The reaction scheme was specifically as follows.
Step 1: Preparation of 5-fluoro-3-nitro-2-(2,2,2-trifluoroacetamido)benzoic acid 2-trifluoroacetamido-5-fluoro-benzoic acid (2.5 g, 10 mmol) was slowly added to fuming nitric acid (14 mL) while in an ice bath. The reaction was continued for 1 hr with stirring while in the ice bath, then poured into ice-water, and filtered, to obtain Compound e: 5-fluoro-3-nitro-2-(2,2,2-trifluoroacetamido)benzoic acid as a white solid (1,9 g, yield 65%). MS (ESI) m/z: [M-Hp-295.
Step 2: Preparation of 2-amino-5-fiuoro-3-nitrobenzoic acid A 10% aqueous sodium hydroxide solution (20 ml.) was added to a solution of Compound e: 5-fluoro~3~nitro-2-(2,2,2-trifluoroacetarnido)benzoic acid (1.18 g, 4 mmol) dissolved in ethanol (20 mL). The reaction was warmed to 80°C and stirred for 3 hrs. Ethanol was removed under reduced pressure, and the residue was adjusted to pH 4 with hydrochloric acid and filtered, to obtain Compound f: 2-ammo-5-fluoro-3-nitrobenzoic acid as a yellow solid (0.72 g, yield 90%). MS (ESI) m/z: [M-H]':: 199.
Step 3: Preparation of methyl 2-amino~5~fiuoro-3-niirobenzoate
Thionyj chloride (2,38g) was slowly added dropwise into a solution of Compound f: 2-amino-5-fluoro-3-nitrobenzoic acid (0.8 g, 4 mmol) dissolved in methanol (20 mL) while in an ice bath, warmed to reflux, and reacted for 8 hrs. After cooling, the solvent was removed under reduced pressure, and the residue was separated by flash column chromatography (petroleum ether: ethyl acetate=5: 1) to obtain Compound g: methyl 2-amino-5-fluoro-3-nitrobenzoate as a yellow solid (0.5 g, yield 58%). MS (ESI) m/z: [M+Hf=215,
Step 4: Preparation of methyl 2,3-diamino-5-fluorobenzoate 10% palladium on carbon (0.7 g) was added to a solution of Compound g: methyl 2-amino-5-fluoro-3-nitrobenzoate (7 g, 32.7 mmol) dissolved in methanol (50 mL), hydrogenated for 7 hrs at room temperature, and filtered. The residue was separated by flash column chromatography (petroleum ether: ethyl acetate=5: 1) to obtain Compound h: methyl 2,3-diamino-5-fluorobenzoate as a yellow solid (2.16 g, yield 36%). MS (ESI) m/z: [M+H]' = 185.
Step 5: Preparation of methyl 6-fluoro-2-oxo-2,3-dihydro-lH~benzimidazole-4-carboxylate
Analogous to the process in Step 1 in Preparation of Compound (1) in Example 1, Compound h: methyl 2,3~diamino~5~fluorobenzoate was cyelized with carbonyldiimidazole (CDI), to obtain Compound i: methyl 6-fluoro-2-oxo-2,3-dihydro-lH-benzimidazole-4-carboxylate (711 mg, yield 37%). MS (ESI) m/z: [M+H]f =211.
Step 6: Preparation of methyl 2-chloro-6-fluoro-lH-benzimidazole-4-carboxylate
Analogous to the process in Step 2 in Preparation of Compound (1) in Example 1, Compound i: methyl 6-fluoro-2-oxo-2,3-dihydro-1 H-benzimidazole-4-carboxylate was chlorinated writh phosphorus oxychloride, to obtain Compound j: methyl 2-chloro-6-fl.uoro-lH-benzimi.dazole-4-carboxylate (681 mg, yield 94%). MS (ESI) m/z: [M+H]+=229.
Step 7: Preparation of methyl 6-fiuoro~2-(piperazin-l~yl)-lH~benzimidazole-4-carboxyiate
Analogous to the process in Step 3 in Preparation of Compound (1) in Example 1,
Compound j: methyl 2-chloro-6-fluoro-lH-benzimidazole-4-carboxylate was subjected to nucleophilic substitution with piperazine, to obtain Compound k: methyl 6-fluoro-2-(piperazin-l-y 1)-lH-benzimidazole-4-carboxylate (430 mg, yield 65%). MS (ESI) m/z: [M+H]+=279.
Step 8: Preparation of 6-fluoro-2-(piperazin-1 -y 1)-1 H-benzimidazole-4-carboxamide
To a solution of Compound k: methyl 6-fluoro-2-(piperazin-l-yl)-lH-benzimidazole-4-carboxylate (100 mg, 0.28 mmol) dissolved in tetrahydrofuran (5 mL), aqueous ammonia (5 mL) was added, warmed to 70°C, sealed, and reacted for 8 hrs. After cooling, the solvent was removed under reduced pressure, and the residue was separated by flash column chromatography (dichloromethane: methanol='10: 1) to obtain Compound 1: 6-fluoro-2-(piperazin-1 -y 1)-1 H-benzimidazole-4-carboxamide as a white solid (20 mg, yield 28%). MS (ESI) m/z: [M+H]+=246.
Step 9: Preparation of 6-fluoro-2-(4-(pyrimidin-4-yl)piperazin-l-yl)-lH-benzimidazole-4-carboxamide
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound 1: 6-fiuoro-2-(piperazm~I-y3)~lH-benzimidazoie~4~carboxarnide was subjected to aromatic nucleophilic substitution with 4-chloropyrimidine, to obtain Compound (16): 6-fluoro-2-(4-(pyrimidin-4-yl)piperazin-l~yl)-lH~benzimidazoie-4-carboxamide (21 mg, yield 48%). LC-MS (ESI), m/z 342 (M+l)+. !H NMR (300MHz, DMSCW/6): 6 12.04 (br, 1H), 9.10 (hr, 1H), 8.52 (s, 1H), 8.22 (d, 1H, J=7.2Hz), 7.71 (br, 1H), 7.33-7.2 (m, 1H), 7.19-7.17 (m, 1H), 6.90 (d, 1H, J=7,2Hz), 3.80 (br, 4H), 3.66 (br, 4H).
Example 17
Preparation of Compound (17): 6-fiuoro-2-(4-(5-fluoropyrinudin-2-yi)piperazin-1 -yi)-1 H-benzimidazole-4-carboxamide
(17)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound 1: 6-fluoro-2-(piperazin-l-yl)-lH-benzimidazole-4-carhoxamide was subjected to aromatic nucleophilic substitution with 2-chloro-5-f]uoropyrimidine, to obtain Compound (17): 6-fluoro-2-(4-(5-fluoropyrimidin-2-yl)piperazin-l-yl)-lH-benzimidazole-4-carboxamide (27 mg, yield 87%).LC-MS (ESI): m/z 360 (M+l)+. !H NMR (300MHz, DMSO-nfd): 6 9.11 (br, 1H), 8.49 (s, 2H), 7.71-7.69 (m, 1H), 7.31-7.28 (m, 1H), 7.18-7.15 (m, 1H), 3.84-3.82 (m, 4H), 3.68-3.65 (m, 4H).
Example 18
Preparation of Compound (18): 2-(4-(5-(dimethylcarbamoyl)pyridin-2-yl)piperazin-l-yl)-6-fluoro-lH-benzimidazole-4-car boxamide
(18)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound 1: 6-fluoro-2-(piperazin-1 -y 1)-1 H-benzimidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 6-chloro-3-dimethylcarbamoylpyridine, to obtain Compound (18): 2-(4-(5-(dimethy3carbamoyl)pyridin-2-y3)piperazin-i-yl)-6-fluoro-lH-benzimidazole-4-car boxamide (14 mg, yield 18%). LC-MS (ESI): m/z 412 (M+l)+. lH NMR (300MHz, DMSO-d6): δ 12,57 (br, 1H), 9.12 (br, III), 8.23 (s, 1H), 7,70-7.63 (rn, 2H), 7.31-7.27 (m, 1H), 7.18-7.14 (m, 1H), 6.94-6.91 (m, 1H), 3.72 (br, 8H), 2,95 (s, 6H).
Example 19
Preparation of Compound (19): 2-(4-(5-cyanopyrimidin-2-yl)piperazin-1 -yl)-6-fluoro- lH-benzimidazole-4-carboxamide
(19)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound 1: 6-fluoro-2-(piperazm-l-yl)-lH-benzimidazoie-4-earboxamide was subjected to aromatic nucleophilic substitution with 2-chlQro-5-cyanopyrimidine, to obtain Compound (19): 2-(4-(5-cyanopynmidin-2-yl)piperazin-l-yl)-6-fluoro-lH-benzimidazole-4-carboxamide (43 mg, yield 77%). LC-MS (ESI): m/z 367 (M+l)+. Ή NMR (300MHz, DMSO-Jd): δ 12.11 (br, 1H), 9.07 (br, III), 8.80 (s, 2H), 7.72 (br, 1H), 7.33-7.29 (m, 1H), 7.20-7.16 (m, 1H), 4.00 (br, 4H), 3.69 (br, 4H).
Example 20
Preparation of Compound (20): 6-fluoro-2-(4-(3-methylcarbamoylpyridin-2-yl)piperazin-l-yl)-lH-benzimidazole-4-carbox amide
(20)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound 1: 6~iluoro-2-(piperazin-l-yl)-lH~benzimidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 2-chloro-N-methylmcotsnamsde. to obtain Compound (20): 6-ffuoro~2-(4-(3-methyjcarbamoylpyridin-2-yl)piperazin~l~yl)-lH~benzimidazole-4~carbox amide (28 mg, yield 52%). LC-MS (ESI): m/z 398 (M+l)+. lH NMR (300MHz, DMSO-<fc): δ 12.21 (br, 1H), 9.10 (br, 1H), 8.41 (br, 1H), 8.26-8.25 (m, 1H), 7.75-7.72 (m, 1H), 7.68 (br, 1H), 7.32-7.28 (m, 1H), 7.18-7.15 (m, IH), 6,96-6.92 (m, IH), 3.69 (br, 8H), 2.79 (s, 3H).
Example 21
Preparation of Compound (21): 6-fluoro-2-(4-(5-trifluoromeihylpyridin-2-yl)piperazin-l-yl)-lH-benzimidazole-4-carboxa mide
(21)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound 1: 6-fluoro-2-(piperazin-l-yl)-lH-benzimidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 2-chloro-5-trifluoromethylpyridine, to obtain Compound (21): 6-fluoro-2-(4-(5-trifluoromethyfpyridin-2-yl)piperazin-l-yl)-lH-benzimidazole-4-carboxa mide (23 mg, yield 52%). LC-MS (ESI): m/z 409 (M+l)+. lH NMR (300MHz, DMSO-i/d): 5 12.32 (br, 1H), 9.10 (br, 1H), 8.44 (s, 1H), 7.85-7.81 (m, 1H), 7.70 (br, 1H), 7.32-7.28 (m, 1H), 7.19-7.15 (m, 1H), 7.06-7.02 (m, 1H), 3.81 (br, 4H), 3.70 (br, 4H).
Example 22
Preparation of Compound (22): 6-fluoro-2-(4-(5-methylcarbamoyipyrimidin-2-yl)piperazin-1-yl)-lH-beiizmiidazole-4-carb oxamide
(22)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound I: 6-fiuoro-2-(piperazin-1-vl)-IH-benzimidazoie-4-carboxamide was subjected to aromatic nucleophilic substitution with 2-chloro-N-methylpyrimidine-5-carboxamide, to obtain Compound (22): 6-fiuoiO-2-(4-(5-methylcarbamoyipynmidin-2-yl)piperazin-j -yl)- lH-benzimidazole-4-carb oxamide (17 mg, yield 29%).LC-MS (ESI): m/z 399 (M+l)+. Ή NMR (300MHz, DMSO-ifc): δ 12,01 (br, 1H), 9.08 (br, 1H), 8.78 (s, 2H), 8.37 (hr, 1H), 7.73 (hr, 1H), 7.34-7.27 (m, 1H), 7.19-7.13 (m, 1H), 3.98 (br, 4H), 3.67 (br, 4H), 2.75 (s, 3H).
Example 23
Preparation of Compound (23): 6-fluoro-2-(4-(6-methylcarbamoylpyridazin-3-yl)piperazin-l-yl)-lH-benzimidazole-4-carb oxamide
(23)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound 1: 6-fluoro-2-(piperazin-l-yl)-lH-benzimidazoie-4-carboxamide was subjected to aromatic nucleophilic substitution with 6~ehloro-N~methylpyridazin-3-carboxamide, to obtain Compound (23): 6-fiuoro-2-(4-(6-methyicarbamoylpyridazin-3-yl)piperazin-l-yl)-lH-benzimidazoie-4-carb oxamide (20 mg, yield 27%). LC-MS (ESI): m/z 399 (M+l)+ lU NMR (300MHz, DMSO-i&amp;5): δ 12.05 (br, 1H), 9.11 (br, 1H), 8.84 (br, 1H), 7.87 (d, 1H, J=10.5Hz), 7.74 (br, 1H), 7.44-7.41 (m, 1H), 7.31 (d, 1H, J=10.5Hz), 7.20-7.17 (m, 1H), 3.90 (br, 4H), 3.72 (br. 4H), 2.80 (s, 3Η).
Example 24
Preparation of Compound (24): 6"fluoro-2-(4-(5-methylcarbamoylpyridin-2-yl)piperazin-1 -yl)- lH-benzimidazole-4-carbox amide
(24)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound 1: 6-fluoro-2-(piperazin-1 -y 1)-1 H-benzimidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 6-chloro-N-methylnicotinamide, to obtain Compound (24): 6-fluoro-2-(4-(5-methylcarbamoylpyridin-2-yl)piperazin-l-yl)-l.H-benzimidazole-4-carbox amide (6 mg, yield 13%). LC-MS (ESI): m/z 398 (M+l)+ lH NMR (300MHz, DMSCW6): 5 12.58 (br, 1H), 9.12 (br, 1H), 8.62 (s, 1H), 8.04-7.98 (m, 1H), 7.72 (s, 1H), 7.32-7.26 (m, 2H), 7.17-7.15 (m, 1H), 6.98-6.92 (m, 1H), 3.75-3.69 (m, 8H), 2.73 (s, 3H).
Example 25
Preparation of Compound (25): 6-fluoro-2-(4-(5-methylcarbamoylpyrazm-2-yl)piperazin-1-yl)-1 H-benzimidazole-4-carbox amide
(25)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound 1: 6-fluoro-2-(piperazin-l-yl)-lH-benzimidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 5~chioro-N~methylpyrazin~2~carboxamide, to obtain Compound (25): 6-fluoro-2'(4-(5-methylcarbamoylpyrazin-2-yi)piperazin-l-yl)-lH-benzimidazole-4-carbox amide (38 mg, yield 64%). LC-MS (ESI): m/z 399 (M+l)+. 1H NMR (300MHz, DMS0-</6): δ 12.05 (br, IH), 9.09 (br, 1H), 8.62 (s, IH), 8.39 (br, 1Π), 8.34 (s, 1H), 7.72 (hr, IH), 7.33- 7.29 (m, IH), 7.19-7.17 (m, IH), 3.88 (br, 4H), 3.70 (br, 4H), 2.77 (s, 3H).
Example 26
Preparation of Compound (26): 2-(4-(5-ethylcarbamoylpyrazin-2-y3)piperazin~1 ~yJ)~6~fiuoro- lH-benzimidazole-4-earboxa mide
(26)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound 1: 6-fluoro-2-(piperazin-l-yl)-lH-benzimidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 5 -chloro-N-ethylpyrazin-2-carboxamide, to obtain Compound (26): 2-(4-(5-ethylcarbamoylpyrazin-2-yl)piperazin-l-yl)-6-fluoro-lH-benzimidazole-4-carboxa mide (19 mg, yield 31%). LC-MS (ESI): m/z 413 (M+l)+. ]H NMR (300MHz, DMSO-d6)\ δ 12.09 (br, IH), 9.11 (br, IH), 8.63 (s, IH), 8.44-8.42 (m, IH), 8.34 (s, IH), 7.73 (br, IH), 7.33- 7.29 (m, IH), 7.20-7.17 (m, IH), 3.87 (br, 4H), 3.71 (br, 4H), 3.28 (q, 2H, J=6.9Hz), 1.09 (t, 3H, J=6.9Hz).
Example 27
Preparation of Compound (27): 6-fluoro-2-(4-(5-isopropylcarbamoylpyrazin-2-yl)piperazin-l-yl)-lH-benzimidazole-4-carb oxamide
(27)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound 1: 6-fluoro-2-(piperazin-l-yl)-IH~benzirnidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 5-chloro-N-isopropylpyrazin-2-carboxamide, to obtain Compound (27): 6-fluorO"2-(4-(5-isopropylcarbamoylpyrazin-2-yl)piperazin-l-yl)-lH-benzimidazole-4-carb oxamide (22 mg, yield 28%). LC-MS (ESI): m/z 427 (M+i)+ lH NMR (300MHz, DMSO-ί/ό): δ 12.04 (br, 1H), 9.09 (br, 1H), 8.63 (s, 1H), 8.32 (s, 111). 8.05-8.00 (m, 1H), 7.70 (br, 1H), 7.34-7.29 (m, 1H), 7.20-7.16 (m, 1H), 4.09 (sep, 1H, j 6.6! iz), 3.88 (br, 4H), 3.71 (br, 4H), 1.15 (d, 6H, J=6.6Hz).
Example 28
Preparation of Compound (28): 2-(4-(5-t-butylcarbamoylpyrazin-2-yl)piperazin-l-yl)-6-fluoro-lH-benzimidazole-4-carbox amide
(28)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound 1: 6-iluoro-2-(piperazin-I-yl)-IH~benzirnidazole-4-carhoxamide was subjected to aromatic nucleophilic substitution with 5-chloro~N-t-butylpyrazin-2-carboxamide, to obtain Compound (28): 2-(4-(5-t-butylcarbamoy lpyrazm-2-y ljpiperazin-1 -y 1)-6-iluoro-1 H-benzimidazole-4-carbox amide (29 mg, yield 35%). LC-MS (ESI): m/z 441 (M+l)+. !HNMR (300MHz, DMSO-i/d): δ 12,04 (br, 1H), 9.09 (br, 1H), 8.62 (s, 1H), 8.31 (s, IH), 7.71 (br, 1H), 7.53 (br, 1H), 7.33-7.29 (m, !H). 7.20-7.16 (m, 1H), 3.86 (br, 4H), 3.71 (br, 4H), 1.37 (s, 9H).
Example 29
Preparation of Compound (29): 6-fluoro-2-(4-(5-(pyrrolin-1 -acyl)pyrazin-2-yl)piperazin-l -yl)-lH-benzimidazole-4-carboxa mide
(29)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound 1: 6-fhroro-2-(piperazin-l-yl)-lH-benzimidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with (5-chloropyrazin-2-yl)(pyrrolin-l-yl)methanone, to obtain Compound (29): 6-fluoro-2-(4-(5-(pyrrolin-l-acyl)pyrazin-2-yl)piperazin-l-yl)-lH-benzimidazole-4-carboxa nude (14mg, yield 17%). LC-MS (ESI): m/z 441 (\! 1}'. ‘H NMR (300MHz, DMSO-i/6): δ 12.04 (br, 1H), 9.08 (br, 1H), 8.51 (s, 1H), 8.34 (s, 1H), 7.71 (br, 1H), 7.33-7.29 (m, 1H), 7.19-7.16 (m, 111). 3.86 (br, 4H), 3.70 (br, 4H), 3.47-3.45 (in, 4H), 1.86-1.83 (in, 4H).
Example 30
Preparation of Compound (30): 6-fluoro-2-(4-(5-(morpholin-4-acyl)pyrazin-2-yl)piperazin-l-yl)-lH-benzimidazole-4-carbo xamide
(30)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound 1: 6-fluoro-2-(piperazin-l-yl)-lH-benzimidazole-4-earboxamide was subjected to aromatic nucleophilic substitution with (5-chloropyrazin-2-yl)(morpholin-2-yl)methanone, to obtain Compound (30): 6-fluoro-2-(4-(5-(pyrroiin~l~acyl)pyrazin-2-yl)piperazm~l ~yl)-lH-benzimidazole-4-carboxa mide (32 mg, yield 37%). LC-MS (ESI): m/z 455 (M+l)+ lH NMR (300MHz, DMSG-J6): 6 12.04 (br, 1H), 9.09 (br, 1H), 8.41 (s, 1H), 8.35 (s, 1H), 7.71 (br, 1H), 7.34-7.30 (m, 1H), 7.20-7.16 (m, 1H), 3.85 (br, 6H), 3.70 (br, 4H), 3.62 (br, 6H).
Example 31
Preparation of Compound (31): 6-fluoro-2-(4-(6-trifluoromethylpyridazin-3 -yl)piperazin-1 -yl)- lH-benzimidazole-4-carbox amide
(31)
Analogous to the process in Step 5 m Preparation of Compound (1) in Example 1, Compound 1: 6-fluoro-2-(piperazin-l-yl)-lH-benzimidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 3-chloro-6-trifluoromethylpyridazine, to obtain Compound (31): 6-fluoro-2-(4-(6-trifluoromethylpyridazin-3-yl)piperazin-l-yl)-lH-benzimidazole-4-carbox amide (15 mg, yield 20%). LC-MS (ESI): m/z 410 (M+l)+. Ή NMR (300MHz, DMSO-i/6): δ 12.05 (br, 1H), 9.10 (br, 1H), 7.94-7.85 (m, 1H), 7.71 (br, 1H), 7.51-7.47 (m, 1H), 7.34-7.30 (m, 1H), 7.21-7.17 (m, 1H), 3.93 (br, 4H), 3.72 (br, 4H).
Example 32
Preparation of Compound (32): 6-fiuoro-2-(4-(6-trifluoromethylpyridine-3-yl)piperazm-1 -yl)-1 H-benzimidazole-4-carboxa mide
(32)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound 1: 6-fluoro-2-(piperazin-l -yl)-lH-benzimidazole-4-carhoxamide was subjected to aromatic nucleophilic substitution with 5-bromo-2-trifiuoromethylpyridine, to obtain Compound (32): 6-fluoro-2-(4-(6-trifluoromethylpyridine-3-yl)piperazin-l-yl)-lH-benzimidazoIe-4-carboxa mide (23 mg, yield 19%). LC-MS (ESI): m/z 409 (Μ · 1)+. ’H NMR (300MHz, DMSO-J6): δ 9.09 (br, 1H), 8.50 (s, 1H), 7.72-7.66 (m, 2H), 7.52-7.48 (m, 1H), 7.33-7.28 (m, 1H), 7.20-7.16 (m, 1H), 3.72 (br, 4H), 3.54 (br, 4H).
Example 33
Preparation of Compound (33): 6-fluoro-2-(4-(2-trifluoromethylpyrimidin-5-yl)piperazin-1 -yl)-lH-benzimidazole-4-carbox amide
(33)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound 1: 6-fluoro-2-(piperazin-1 -y 1)-1 H-benzimidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 5-bromo-2-trifluoromethylpyrimidine, to obtain Compound (33): 6-fluoro-2-(4-(2-trifluoromethylpyrimidin-5-yl)piperazin-l-yl)-lH-benzimidazole-4-carbox amide (12 mg, yield 16%). LC-MS (ESI): m/z 410 (M+l)+. 1H NMR. (300MHz, DMSO-ifc): 6 12,04 (br, 1H), 9.09 (br, IB), 8.69 (s, 2H), 7.71 (br, 1H), 7.32-7.29 (m, 1H), 7.20-7.17 (m, 1H), 3.73 (br, 411). 3.62 (br, 4P1).
Example 34
Preparation of Compound (34): 6-fluoro-2-(4-(5-trifluoromethylpyrimidin-2-yl)piperazin-l-yl)"lH-benzimidazole-4-carbox amide
(34)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound 1: 6-fluoro-2-(piperazin-l -yl)-l H-benzimidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 2-chloro-5-trifluoromethylpyrimidine, to obtain Compound (34): 6-fiuoro-2-(4-(5-trifiuoromeihyipyrimidm-2-yl)piperazin-l-yl)-lH-benzimidazole-4-carbox amide (8 mg, yield 14%). LC-MS (ESI): m/z 410 (M+l)+ ]H NMR (300MHz, OMSO-d6): δ 12.02 (br, 1H), 9.09 (br, 1H), 8.75 (s, 2H), 7.72 (br, 1H), 7.33-7.29 (m, 1H), 7.20-7.17 (m, 1H), 4.00 (br, 4H), 3.69 (br, 4H).
Example 35
Preparation of Compound (35): 6-ffuoro-2-(4-(5-trifluoromethylpyrazin-2-yl)piperazin-l-yl)-lH-benzimidazole-4-carboxa mide
(35)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound 1: 6-fluoro-2-(piperazin-I-yl)-lH-benzimidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 2-chloro-5-trifiuoromethylpyrazine, to obtain
Compound (35): 6-fiuoiO-2-(4-(5-trifluoromethyipyrazin-2-yl)piperazin-l-yl)-lH-benzimidazoie-4-carboxa mide (60 mg, yield 90%). LC-MS (ESI): m/z 410 (M+l)+. !H NMR (300MHz, DMSO-i/6): δ 12.04 (br, 1H), 9.09 (br, 1H), 8.51 (s, 1H), 8.50 (s, 1H), 7.71 (br, 1H), 7.33-7.30 (m, 1H), 7.20-7.17 (m, 1H), 3.89 (br, 4H), 3.71 (br, 4H).
Example 36
Preparation of Compound (36): 2-(4-(5-dimethylcarbamoylpyrazm-2-yl)piperazin-1 -yl)-6-fluoro- lH-benzimidazole-4-carb oxamide
(36)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound 1: 6-fluoro-2-(piperazm-l-yl)-lH-benzitnidazole-4-earboxamide was subjected to aromatic nucleophilic substitution with 5-chloro-N,N-dimethylpyrazin-2-earboxamide, to obtain Compound (36): 2-(4-(5-dimethylcarbamoy lpyrazin-2-yl)piperazin-1 -yl)-6-fluoro- lH-benzinudazole-4-carb oxamide (29 mg, yield 37%). LC-MS (ESI): m/z 413 (M+l)+. !H NMR (300MHz, DMSO~d6): 6 12.02 (br, 1H), 9.09 (br, 1H), 8.37 (s, 1H), 8.34 (s, 1H), 7.71 (br, 1H), 7.33-7.30 (m, 1H), 7.20-7.16 (m, 1H), 3.83 (br, 4H), 3.73 (br, 1H), 3.07 (s, 3H), 2.98 (s, 3H).
Example 37
Preparation of Compound (37): 2-(4-(5-cyanopyrazin-2-yl)piperazin-l-yi)-6-fluoro-lH-benzimidazole-4-earboxamide
')
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound 1: 6-fluoro-2-(piperazin-l-yl)-lH-benzimidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 5-ch!oro-2-cyanopyrazine, to obtain Compound (37): 2-(4-(5-cyanopyrazm-2-yl)piperazin-1 -yl)-6-fluoro-lH-benzimidazole-4-carboxamide (40 mg, yield 58%). LC-MS (ESI): m/z 367 (M+l)+. Ή NMR (300MHz, DMS0-./6): δ 12.05 (br, 1H), 9.07 (br, 1H), 8.59 (s, 1H), 8.49 (s, 1H), 7.69 (s, 1H), 7.33-7.29 (m, 1H), 7.20-7.16 (m, 111). 3.93 (br, 4H), 3.71 (br, 4H).
Example 38
Preparation of Compound (38): 2-(4- (2-cyanopy r i rn d i n-5 y 1 )p ip erazm-1 - y 1)- 6 - f! u o ro -1H benzi m idazo le-4-carboxami de
(38)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example I, Compound 1: 6-fluoro-2-(piperazin-l-yl)-lH-benzimidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 5-bromo-2-cyanopyrimidine, to obtain Compound (38): 2-(4-(2-cyanopyrimidin-5-yl)piperazin-l-yl)-6-fluoro-lH-benzimidazole-4-carboxamide (18 mg, yield 26%). LC-MS (ESI): m/z 367 (M+l)+. SH NMR (300MHz, DMSO-r/ό): δ 12.03 (br, 1H), 9.08 (br, 111). 8.63 (s, 2H), 7.73-7.65 (m, 1H), 7.33-7.29 (m, 1H), 7.22-7.17 (m, 1H), 3.73-3.69 (m, 8H).
Example 39
Preparation of Compound (39): 6-fiuoro-2-(4-(2-methylcarbamoyipyrimidin-2-yl)piperazin-5-yl)-lH-benzimidazole-4-carb oxamide
(39)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example l, Compound 1: 6-fluoro-2-(piperazm-l-yl)-lH-benzimidazole-4-carboxamide was subjected to aromatic nucleophilic substitution with 5-brQmo-N-methylpyrinudine-2-earboxamide, to obtain Compound (39): 6-fluoro-2-(4-(2-methylcarbamoylpyrimidin-2-yl)piperazine“5-yl)-lH-benzimidazole-4-car boxamide (16 mg, yield 29%). LC-MS (ESI): m/z 399 (M+l)+. lH NMR (300MHz, DMSO-ί/ό): 6 12.02 (br, 1H), 9.08 (hr, 1H), 8.67 (s, 2H), 8.34 (br, 1H), 7.71 (br, 1H), 7.33-7.27 (m, 1H), 7.19-7.12 (m, 1H), 3.99 (br, 4H), 3.68 (br, 4H), 2.72 (s, 3H).
Example 40
Preparation of Compound (40): 2-(4-(2-ethylcarbamoylpyrimidin-5-yl)piperazin-l-yl)-6-fluoro-lH-benzimidazole-4-carbox amide
(40)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound 1: 6~fiuoro~2-(piperazin-1~yl)-IH-benzimidazoie-4-carboxarnide was subjected to aromatic nucleophilic substitution w'ith 5-bromo-N-ethylpyrimidine-2-earboxamide, to obtain Compound (40): 2-(4-{2-etby3carbamoy]pyrimidin~5~yl)piperazin-l~yl)-6-fluoro-lH-benzimidazole-4-carbox amide (17 mg, yield 23%). LC-MS (ESI): m/z 413 (M+l)+ lU NMR (300MHz, DMSO^d): 6 12.01 (br, 1H), 9.09 (br, 1H), 8.64 (s, 2H), 8.31 (hr, 1Π), 7.72 (br, 1Π), 7.34-7.27 (m, 1H), 7.19-7.13 (m, !H), 3.96 (br, 4H), 3.65 (br, 4H), 3.26 (q, 2H, J=6,9Hz), 1.07 (t, 3H, J=6.9Hz).
Example 41
Preparation of Compound (41): 2-(4-(2-dimethylcarbamoy lpyrimidin-5-yl)piperazin-1 -yl)-6-fluoro-1 H-benzimidazole~4-ca rboxamide
(41)
Analogous to the process in Step 5 in Preparation of Compound (1) in Example 1, Compound 1: 6-fluoro-2-(piperazm-l-yl)-lH-benzimidazole-4-earboxamide was subjected to aromatic nucleophilic substitution with 5-bromo-N-dimethylpyrirnidin-2-carboxamide, to obtain Compound (41): 2-(4-(2-dimethylcarbamoylpyrimidin-5-yf)piperazin-1 -yl)-6-fluoro-1 H-benzimidazole-4-ca rboxamide (19 mg, yield 26%). LC-MS (ESI): m/z 413 (MH)+ Ή NMR (300MHz, DMSO~d6): δ 12.03 (br, 1H), 9.07 (br, 1H), 8.63 (s, 2H), 8.32 (br, 1H), 7.72 (br, 1H), 7.31-7.26 (m, 1H), 7.18-7.13 (m, 1H), 3.97 (br, 4H), 3.67 (br, 4H), 3.08 (s, 3H), 2.97 (s, 3H).
Biological evaluation
Experimental principle:
Poly(ADP-ribosyl)ation of nuclear proteins is a post-translational modification occurred in response to DNA damage. PARP is the abbreviation of poly(ADP-ribose) polymerase, which catalyzes the attachment of poly(ADP-ribose) to an adjacent nuclear protein in the presence of NAD, thus eliciting a mechanism of DNA repair through base excision repair pathway. The level of biotin-labeled ADP-ribose binding to histone can be detected by using the HT Universal Chemiluminescent PARP Assay Kit commercially available from Trevigen Corp,
Reagents and materials 1 jjnjversaf Chemiluminescent PARI* Assay Kit wdth Histone-coated Strip Wells, commercially available from Trevigen (US), Catalog #: 4676-096-K. 2. Plate reader: EnVision Multilabel Plate Reader available from Perkin Elmer (US).
Solutions and buffers 1. Washing buffer: 0.1% Triton X-100 in PBS. 2. 20X PARP buffer - It was 1:20 diluted in deionized water to obtain a IX buffer, which was used for diluting the recombinant PARI* enzyme, PARI* Cocktails, and test compounds. 3. 10X PARP Cocktail was formulated into a IX PARP Cocktail by mixing 1 OX PARP Cocktail 2.5 μΐ/well, 10X activated DNA 2.5 μΙ/well, and IX PARP buffer 20 pl'well. 4. The PARP enzyme was carefully diluted with the IX PARP buffer just before use, the diluted enzyme solution should be used as quickly as possible and the remaining solution should be discarded. 5. Strep-HRP was 1:500 diluted with the IX Strep diluent just before use to obtain a IX solution. 6. The chemiluminescent substrate was prepared just before use, by uniformly mixing equal volume of PeroxyGlow A and B to obtain a substrate for horseradish peroxidase.
Experimental method
Formulation of compound solutions 1. 10 mM stock solution of each test compound was diluted to 10 μΜ, and 1 μΜ in DMSO. 2. Just before experiment, the solution at various concentration gradients of each compound dissolved in DMSO was 1:20 diluted in the IX PARP buffer, to obtain a 5X compound solution for test. The positive and negative control wells contained the IX PARP buffer (containing 5% DMSO).
Experimental procedures 1. 50 μΐ of IX PARP buffer per well was added to infiltrate the histone, and the plate was incubated for 30 min at room temperature. Then the IX PARP buffer in each well was aspirated, and the remaining liquid was tapped dry on paper towels. 2. The diluted 5X solutions of Compounds (1) to (37) were added to respective wells (10 μΐ per well). The positive and negative control wells contained the IX PARP buffer (containing 5% DMSO). 3. The PARP enzyme was diluted in the IX PARP buffer to give a concentration of 0.5 Unit per 15 μΐ, and then 15 μί of the enzyme solution was added to each well except that the negative control well was added exclusively with the IX PARP buffer. The plate was incubated for 10 min at room temperature. 4. 25 μί of the IX PARP Cocktail was sequentially added to each well. 5. The plate was incubated for 60 min at 27°C. 6. After incubation, the reaction solution was aspirated from the wells, and the remaining liquid was tapped dry on paper towels. Then, the plate was washed 4 times with 0. i°/b Triton X-100 in PBS (200 μί per well per wash), and the remaining liquid was tapped dry on paper towels. 7. Subsequently, the diluted IX Strep-HRP solution was added to each well, and then the plate was incubated for 60 min at 27°C. 8. After incubation, the reaction solution was aspirated from the wells, and the remaining liquid was tapped dry' on paper towels. Then, the plate was washed 4 times with 0.1% Triton X-100 in PBS (200 μί per well per wash), and the remaining liquid was tapped dry on paper towels. 9. After washing, equal volume of the PeroxyGlow A and B solutions were uniformly mixed, 100 μΐ of the solution was added to each well, and the chemiluminescent signals were recorded on a plate reader immediately.
Data processing
The readout of each well is converted into the percent inhibition The percent inhibition of the compounds may be calculated by an equation below:
Note: the readout of the positive control well is designated as 100% enzyme activity; the readout of the negative control well is designated as 0% enzyme activity; and the activity X refers to the readout from respective concentration of each sample.
Table 1. Inhibition of t he compounds on PARP-1 enzyme
The data given in Table 1 fully suggests that the compounds of the present invention are all PARP-1 inhibitors. As indicated in the examples, the IC50 value of Compounds (1), (2), (5), (6), (7), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21), (22), (23), (24), (25), (26), (27), (28), (29), (30), (31), (32), (33), (34), (35), (36), (37), (38), (39), (40), and (41) is not greater than 100 nM, and the IC50 value of Compounds (16), (19), (25), (26), (30), (31), (33), (35), (36), (37), (38), (39), (40), and (41) is further not greater than 10 nM.
Comprises/comprising” and ‘‘includes/ineluding’’ when used in this specification is taken to specify the presence of stated features, integers, steps or components but does not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof. Thus, unless the context clearly requires otherwise, throughout the description and the claims, the words ‘comprise’, ‘comprising’, ‘includes’, including’ and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to”.

Claims (16)

1. A benzimidazole-2-piperazine heterocyclic compound of general Formula (I) or a pharmaceutically acceptable salt thereof:
wherein in general Formula (I): R is fluoro; one of X, Y, and Z is nitrogen, and the others are CH; or X, Y, and Z are all CH; Ri is hydrogen, C i -C6 alkyl, methoxy, trifluoromethyl, halo, nitro, cyano, CONR2R3, and NR2R3; R2 is hydrogen, or C1 -C6 alkyl; and R3 is hydrogen, C1 -C6 alkyl, or C3-C6 cycloalkyl, or NR2R3 are cyclized to form morpholinyl, tetrahydropyrrolyl, and piperidinyl.
2. The benzimidazole-2-piperazine heterocyclic compound of general Formula (I) according to claim 1, wherein R is fluoro; one of X, Y, and Z is nitrogen, and the others are CH; or X, Y, and Z are all CH; Ri is hydrogen, C1-C4 alkyl, methoxy, trifluoromethyl, fluoro, nitro, cyano, CONR2R3, and NR2R3; R2 is hydrogen, or C1-C4 alkyl; and R3 is hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl, or NR2R3 are cyclized to form morpholinyl, and tetrahydropyrrolyl.
3. The benzimidazole-2-piperazine heterocyclic compound of general Formula (I) according to claims 1 or 2, which is Compounds (16)-(41) below:
4. The benzimidazole-2-piperazine heterocyclic compound according to claim 1, wherein the pharmaceutically acceptable salt is a hydrochloride, a sulfate, a phosphate, an acetate, a trifluoroacetate, a methanesulfonate, a trifluoromethanesulfonate, a p-toluenesulfonate , a tartrate, a maleate, a fumarate, a succinate or a malate of the compound of general Formula (I).
5. A method for preparing the compound of general Formula (I) according to claim 1, by a reaction scheme below:
wherein R and Ri are as defined above; the method comprising specifically: Step 1): cyclizing substituted methyl 2, 3-diaminobenzoate with carbonyldiimidazole, to obtain substituted methyl 2-oxo-2,3-dihydro-lH-benzimidazole-4-carboxylate (II); Step 2): chlorinating the substituted methyl 2-oxo-2,3-dihydro-lH-benzimidazole-4-carboxylate (II) obtained in Step 1) through reaction with phosphorus oxychloride, to obtain substituted methyl 2-chloro-1 H-benzimidazole-4-carboxylate (III); Step 3): subjecting the substituted methyl 2-chloro-lH-benzimidazole-4-carboxylate (III) obtained in Step 2) to nucleophilic substitution with piperazine in the presence of a base, to obtain substituted methyl 2-(piperazin-1 -yl)-1 H-benzimidazole-4-carboxylate (IV); Step 4): aminolyzing the ester group of the substituted methyl 2-(piperazin-l-yl)-lH-benzimidazole-4-carboxylate (IV) obtained in Step 3) in a methanolic ammonia solution, to obtain substituted 2-(piperazin-l-yl)-lH-benzimidazole-4-carboxamide (V); and Step 5): coupling the substituted 2-(piperazin-l-yl)-lH-benzimidazole-4-carboxamide (V) obtained in Step 4) with an acid, or reductively aminating the substituted 2-(piperazin-l-yl)-lH-benzimidazole-4-carboxamide (V) obtained in Step 4) with an aldehyde, to generate the compound of general Formula (I).
6. A pharmaceutical composition comprising a therapeutically effective amount of the compound of general Formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and/or diluents.
7. The pharmaceutical composition according to claim 6, which is prepared into tablets, capsules, an aqueous suspension, an oily suspension, a dispersible powder, granules, lozenges, an emulsion, a syrup, a cream, an ointment, a suppository, or an injection.
8. Use of the compound of general Formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claims 6 or 7, in the manufacture of a medicament for treatment and/or prevention of diseases that are ameliorated through inhibition of the PARP activity.
9. The use according to claim 8, wherein the diseases that are ameliorated through inhibition of the PARP activity are selected from the group consisting of vascular diseases, septic shock, ischemic damage, neurotoxic symptoms, hemorrhagic shock, inflammatory disease, and multiple sclerosis.
10. Use of the compound of general Formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof in the manufacture of adjuvant drugs for treatment and/or prevention of tumors.
11. Use of the compound of general Formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for boosting tumor radiotherapy.
12. Use of the compound of general Formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof in the manufacture of chemotherapeutic agents for the treatment and/or prevention of tumors.
13. Use of the compound of general Formula (I) according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claims 6 or 7, in the manufacture of a medicament for the treatment and/or prevention of cancer in an individual, wherein the cancer is deficient in Homologous Recombination (HR) dependent DNA double strand break (DSB) repair.
14. The use according to claim 13, wherein the cancer comprises one or more cancer cells having a reduced or abrogated ability to repair DNA DSB by HR relative to normal cells.
15. The use according to claim 13, wherein the cancer has a BRCA-1 or BRCA-2 deficient mutant phenotype.
16. The use according to claim 13, wherein the cancer is breast, ovary, pancreas or prostate cancer.
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LT3325623T (en) 2015-07-23 2019-10-25 Inst Curie Use of a combination of dbait molecule and parp inhibitors to treat cancer
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003106430A1 (en) * 2002-06-14 2003-12-24 Pfizer Inc. Benzimidazole inhibitors of poly(adp-ribosyl) polymerase
US20070265324A1 (en) * 2006-01-17 2007-11-15 Wolfgang Wernet Combination Therapy with Parp Inhibitors

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK0841924T3 (en) * 1995-08-02 2003-02-10 Univ Newcastle Ventures Ltd benzimidazole
DE19745692A1 (en) 1997-07-24 1999-01-28 Bayer Ag Process for the preparation of 2-chloro-benzimidazole derivatives
CN1331683A (en) * 1998-11-17 2002-01-16 巴斯福股份公司 2-phenylbenzimidazoles and 2-phenylindoles, and prodn. and use thereof
DE19920936A1 (en) 1999-05-07 2000-11-09 Basf Ag Heterocyclically substituted benzimidazoles, their preparation and use
YU7203A (en) 2000-08-08 2006-01-16 Sanofi-Aventis Benzimidazole derivatives, preparation and therapeutic use thereof
FR2833948B1 (en) * 2001-12-21 2004-02-06 Sod Conseils Rech Applic NOVEL BENZIMIDAZOLE DERIVATIVES AND THEIR USE AS MEDICAMENTS
CN1223590C (en) 2002-09-30 2005-10-19 天津天士力集团有限公司 Prepn process of pipecolinate
CN101511821B (en) * 2006-05-02 2013-07-17 Abbvie公司 Substituted 1H-benzimidazole-4-carboxamides are potent PARP inhibitors
US8067613B2 (en) * 2007-07-16 2011-11-29 Abbott Laboratories Benzimidazole poly(ADP ribose)polymerase inhibitors
US9073893B2 (en) * 2011-07-26 2015-07-07 Nerviano Medical Sciences S.R.L. 3-Oxo-2,3-dihydro-1H-indazole-4-carboxamide derivatives as PARP-1 inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003106430A1 (en) * 2002-06-14 2003-12-24 Pfizer Inc. Benzimidazole inhibitors of poly(adp-ribosyl) polymerase
US20070265324A1 (en) * 2006-01-17 2007-11-15 Wolfgang Wernet Combination Therapy with Parp Inhibitors

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